The present disclosure provides methods, compositions, and systems for profiling epitranscriptomic RNA modifications in a cell. The present disclosure also provides methods for profiling interactions between one or more RNAs of interest in a cell and an RNA-binding protein (e.g., a protein that introduces an epitranscriptomic modification on an RNA of interest). Also provided by the present disclosure are methods for diagnosing a disease or disorder in a subject based on a profile of epitranscriptomic RNA modifications or a profile of interactions between an RNA binding protein and RNAs in a cell, including cells within an intact tissue. Methods of screening for or testing a candidate agent capable of modulating epitranscriptomic modification of one or more RNAs or interactions between one or more RNAs and an RNA-binding protein are also provided by the present disclosure. The present disclosure also provides methods for treating a disease or disorder in a subject in need thereof. Pairs of probes and sets of probes comprising oligonucleotide portions, which may be useful for performing the methods described herein, are also described by the present disclosure. Additionally, the present disclosure provides kits comprising any of the probes described herein.
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
C40B 70/00 - Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or barcodes
2.
COMPOSITIONS AND METHODS FOR HIGH-RESOLUTION SPATIAL GENOMICS IN FIXED TISSUES WITH ENHANCED DNA-BARCODED ARRAYS
Methods and compositions for altering the distribution of solid supports within an array are provided herein, for benefit of enhancing utility of such arrayed solid supports in various applications. Certain aspects feature improved spatial arrays including distinct populations of solid supports with unique barcode sequences; methods for enhancing uniform distribution of solid supports in an array; methods for preparing fixed tissue samples (e.g., formalin-fixed paraffin-embedded (FFPE) tissue samples) for barcode penetration and immunostaining using neutral proteases; and methods for coating tissue samples with a positive charge for enhanced barcoded array applications, among others.
Tandem Interspaced Guide RNA (TIGR) systems are disclosed that offer a unique RNA-guided mechanism for genome manipulation with several distinct advantages over existing CRISPR systems. Conserved across bacteria and viruses, TIGR arrays have a dual repeat architecture that, once transcribed into precursor RNA, are processed into 36-nt tigRNAs that bind to Nop domain-containing TIGR-associated nuclease proteins, or "Tas" proteins. TigRNAs act as guide RNAs, directing the tigRNA-Tas complex to a target nucleotide sequence where tandem spacer interactions with complementary sequences on both strands of a target nucleotide sequence result in a staggered double-strand DNA cleavage. Unlike CRISPR, TIGR systems do not depend on PAM or similar sequence elements, allowing flexible target site selection. Tas proteins are also shown to cleave target sequences in human cells. The modular structure of TIGR and lack of targeting motif requirements, TIGR is a powerful tool for programmable DNA cleavage and base/prime editing systems.
Tandem Interspaced Guide RNA (TIGR) systems are disclosed that offer a unique RNA-guided mechanism for genome manipulation with several distinct advantages over existing CRISPR systems. Conserved across bacteria and viruses, TIGR arrays have a dual repeat architecture that, once transcribed into precursor RNA, are processed into 36-nt tigRNAs that bind to Nop domain- containing TIGR-associated nuclease proteins, or "Tas" proteins. TigRNAs act as guide RNAs, directing the tigRNA-Tas complex to a target nucleotide sequence where tandem spacer interactions with complementary sequences on both strands of a target nucleotide sequence result in a staggered double-strand DNA cleavage. Unlike CRISPR, TIGR systems do not depend on PAM or similar sequence elements, allowing flexible target site selection. Tas proteins are also shown to cleave target sequences in human cells. The modular structure of TIGR and lack of targeting motif requirements, TIGR is a powerful tool for programmable DNA cleavage and base/prime editing systems.
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
The present disclosure provides methods and systems for the simultaneous profiling of the RNA transcriptome and translatome in a single cell. Also provided by the present disclosure are methods for diagnosing a disease or disorder in a subject based on a profile of the RNAs being translated in a cell, including cells within an intact tissue. Methods of screening for or testing a candidate agent capable of modulating translation of one or more RNAs are also provided by the present disclosure. The present disclosure also provides methods for treating a disease or disorder in a subject in need thereof. Sets of probes comprising oligonucleotide portions, which may be useful for performing the methods described herein, are also described by the present disclosure. The present disclosure further provides non-naturally- occurring assembled ribosome complexes comprising ribosome subunits and oligonucleotide probes. Additionally, the present disclosure provides kits comprising any of the probes described herein.
Variant identification in the presence of alignment artifacts is described. Discordant reads of sequencing data may be identified with respect to a reference sequence. A variant-indicative signal may be generated based at least in part on a subread analysis of the discordant reads, the variant-indicative signal including one or both of a discordant junction signal or an alignment generated using a latent breakpoint graph. A variant call may be generated based at least in part on the variant-indicative signal, the variant call identifying a structural variant in the sequencing data as compared to the reference sequence.
Described herein are muscle-specific targeting moieties and compositions including the muscle specific targeting motifs. Also described herein are uses of the muscle-specific targeting motifs and compositions including the muscle specific targeting moieties. In some embodiments, the muscle-specific targeting moieties and compositions including the muscle specific targeting moieties can be used to direct delivery of a cargo to a muscle cell.
The present disclosure provides methods and systems for the super-resolution (SR) imaging of polysomes in a single cell. Also provided by the present disclosure are methods for diagnosing a disease or disorder in a subject based on a polysome structure profile in a cell, including cells within an intact tissue. Methods of screening for or testing a candidate agent capable of modulating polysome structure are also provided by the present disclosure. The present disclosure also provides methods for treating a disease or disorder in a subject in need thereof. Sets of probes comprising oligonucleotide portions, which may be useful for performing the methods described herein, are also described by the present disclosure. The present disclosure further provides non-naturally-occurring assembled ribosome complexes comprising ribosome subunits and oligonucleotide probes. Additionally, the present disclosure provides kits comprising any of the probes described herein.
The present disclosure provides methods of using a prime editor in combination with prime editing guide RNAs (pegRNAs) and, optionally, nicking gRNAs to carry out prime editing to directly correct mutations (i.e., c.1412delA) in the CDKL5 gene that cause CDKL5 deficiency disorder. The present disclosure also provides compositions, complexes, and systems comprising the pegRNAs, nicking gRNAs, and/or prime editors disclosed herein, as well as polynucleotides and vectors encoding the same, and cells, kits, and pharmaceutical compositions comprising the same.
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
A61K 31/7105 - Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
A61P 25/00 - Drugs for disorders of the nervous system
C12N 7/04 - Inactivation or attenuationProducing viral sub-units
Provided herein are methods and compositions for screening of multiple nucleic acid sites, such as functional non-coding transcriptional regulatory elements in a cell. In particular, provided are methods and compositions, comprising: delivering to a cell a composition comprising: a single guide RNA (sgRNA) or a polynucleotide encoding the sgRNA comprising a sequence capable of hybridizing with a target sequence present in a non-coding transcriptional regulatory element, and an effector protein or one or more nucleotide sequences encoding the effector protein optionally comprising an effector domain, wherein the sgRNA hybridizes to the target sequence and forms a complex with the effector protein; and measuring gene expression upon binding of the complex to the target sequence.
Applicants have synthesized and evaluated several bifunctional molecules targeting both the complement immune system and surface proteins of the opportunistic bacterial pathogens, which poses significant health threats to humans. From this, Applicants isolated a compound that effectively activated complement immunity to inhibit bacterial growth. Furthermore, Applicants developed a robust testing platform for complement-recruiting compounds, allowing the streamlined assessment of ternary complex formation and the efficacy of novel bifunctional molecules for recruiting the complement immune system and inhibiting bacterial growth. These findings demonstrate the potential of this approach in combating antibiotic-resistant infections, with implications for other bacterial pathogens or diseases.
C07D 291/08 - Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
C07D 419/14 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
C07D 515/22 - Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups , or in which the condensed system contains four or more hetero rings
The Trustees of Columbia University in the City of New York (USA)
The Broad Institute, Inc. (USA)
Inventor
Quinn, Peter M. J.
Lopes Da Costa, Bruna
Tsang, Stephen H.
Liu, David R.
Abstract
The present disclosure provides systems, methods, and compositions for modifying the crumbs homologue-1 gene. Particularly the present disclosure provides systems, methods, and compositions for prime editing insertion or correction of mutations in the crumbs homologue-1 gene.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
A61K 38/17 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans
The present invention generally relates to compositions, methods applications and screens used in functional genomics that focus on gene function in a cell and that may use vector systems and other aspects related to Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas systems and components thereof. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for utilizing the CRISPR-Cas system.
Noncanonical peptides associated with cancers, including pancreatic cancer, that can be presented by human leukocyte antigens class I, T cell receptors that recognize such peptides, and uses for such peptides, T cell receptors and the nucleotide sequences that encode them in methods of activating immune cells and treating subjects with cancer are described herein.
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
The present disclosure provides a method for correcting SCN1A mutations linked to Dravet syndrome that uses adenine base editors. The disclosure provides compositions and methods, including adenine base editors (ABEs), guide RNAs, complexes, nucleic acid molecules, vectors, delivery systems, and pharmaceutical compositions aimed at targeting SCN1A mutations.
Described in certain example embodiments herein are compositions, such as immunogenic compositions that can contain or more viral polynucleotides and/or polypeptides. In some embodiments, the one or more viral polynucleotide is a non-canonical viral open reading frame (ORF). Also described herein are methods to identify one or more viral polynucleotides and/or polypeptides such as a non-canonical viral ORF, such as massively parallel ribosome profiling.
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in prokaryotic and eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity.
Described herein are muscle-specific targeting moieties and compositions including the muscle specific targeting motifs. Also described herein are uses of the muscle-specific targeting motifs and compositions including the muscle specific targeting moieties. In some embodiments, the muscle-specific targeting moieties and compositions including the muscle specific targeting moieties can be used to direct delivery of a cargo to a muscle cell.
In certain aspects, provided herein are mutant stimulator of interferon genes (STING) polypeptides, compositions thereof and methods of using the same, wherein the mutation is within the dimerization interface of the STING, and wherein the mutation reduces the ability of the mutant STING polypeptide to mediate protein leakage across a membrane compared to a wild-type STING polypeptide.
Aspects of the present disclosure generally relate to systems, compositions, and methods for prime editing with improved editing efficiency and/or reduced indel formation by inhibiting one or more genes of interest while conducting prime editing of a target site. Accordingly, the present disclosure provides systems, compositions and methods for editing a nucleic acid molecule by prime editing that involves contacting a nucleic acid molecule with a prime editor, one or more pegRNAs, and an inhibitor of a gene of interest, thereby installing one or more modifications to the nucleic acid molecule at a target site with increased editing efficiency and/or lower indel formation. The present disclosure further provides polynucleotides for editing a DNA target site by prime editing comprising a nucleic acid sequence encoding a napDNAbp, a polymerase, and an inhibitor of one or more genes of interest, wherein the napDNAbp and polymerase is capable in the presence of a pegRNA of installing one or more modifications in the DNA target site with increased editing efficiency and/or lower indel formation. The disclosure further provides, vectors, cells, and kits comprising the compositions and polynucleotides of the disclosure.
The present disclosure provides methods, compositions, and systems for evolving virus-like particles (VLPs) having one or more desired properties such as increased production levels, increased cargo packaging efficiency, and/or increased transduction of particular target cell types of interest. The present disclosure also provides libraries for use in such methods, and methods for producing the libraries. Group specific antigen (gag) proteins comprising nucleocapsid protein variants evolved using the methods described herein are also provided herein. The present disclosure also provides VLPs comprising such gag proteins comprising nucleocapsid protein variants. Polynucleotides, vectors, cells, and kits useful for performing the methods described herein are also provided.
Described herein are compositions for treatment of vaginal dysbiosis (e.g., bacterial vaginosis), symptoms of vaginal dysbiosis (e.g., bacterial vaginosis), or conditions/disorders associated with vaginal dysbiosis (e.g., bacterial vaginosis). Also disclosed herein are methods for treating vaginal dysbiosis (e.g., bacterial vaginosis) in an individual in need thereof, methods for reducing the risk of vaginal dysbiosis (e.g., bacterial vaginosis) in an individual in need thereof, methods for preventing recurrence of vaginal dysbiosis (e.g., bacterial vaginosis) in an individual treated for a prior episode of vaginal dysbiosis (e.g., bacterial vaginosis). Also described are methods for restoring Lactobacillus dominated microbiota, including L. crispatus-dominated microbiota or microbiota dominated by other non-iners Lactobacillus species, in an individual in need thereof.
A61K 31/201 - Carboxylic acids, e.g. valproic acid having a carboxyl group bound to an acyclic chain of seven or more carbon atoms, e.g. stearic, palmitic or arachidic acid having one or two double bonds, e.g. oleic or linoleic acid
A61K 31/7056 - Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
According to some embodiments, the cell culture system allows for the passage of cells in high-throughput cell culture applications. Unlike enzymatic detachment processes, the cell culture system, in some embodiments, limits any imparted damage onto the cell. Additionally, the lack of reliance on enzymes for cell detachments (e.g. trypsin) reduces and/or prevents the accrual of genetic mutations that can occur during enzymatic detachment processes. The cell culture system, in some embodiments, is capable of passaging and/or detaching cells at rates convenient for high throughput cell culturing and/or automated cell culturing regimes. Advantageously, the cell culture system, in certain embodiments, provides sufficient adhesion to promote cell growth and proliferation, but is capable of reducing the adhesion between the cell and the surface upon application of the electric field.
Provided herein is a rAAV-mediated TSC2 "split intein" gene therapy that uses two separate rAAV particles, each engineered to deliver a different portion of the human TSC2 coding sequence, to target cells of the CNS such that, when co-expressed, the two portions of the TSC2 protein join via intein-mediated protein splicing to form a full length human TSC2 (tuberin) protein that exhibits TSC2 activity; viral particles (rAAV particles) for use therewith; methods of production, and methods of use, including methods for treating Tuberous Sclerosis Complex (TSC) caused by TSC2 gene mutations and symptoms arising therefrom; and kits.
The subject matter disclosed herein is generally directed to methods for highly multiplexed spatially resolved optical perturbation screening and kits thereof. The methods use sequence specific perturbations that can be amplified in situ and optically decoded. The perturbations can be paired with optically decoded gene expression data.
Systems, methods and composition for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising novel Fanzor polypeptides and a reprogrammable targeting nucleic acid component and methods and application of use are described.
C12N 9/78 - Hydrolases (3.) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
C12Q 1/34 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving hydrolase
C12Q 1/48 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving transferase
Engineered, non-naturally occurring, RNA-targeting Type V Cas polypeptides lacking collateral cleavage activity, compositions thereof, CRISPR-Cas systems thereof, packaging and delivery systems thereof, kits thereof, and methods of use thereof, for modifying target RNA. The Type V Cas polypeptide may be a Cas12 polypeptide, optionally a Cas12a2 polypeptide. The compositions may comprise the Type V Cas polypeptide and an engineered polypeptide comprising a tetratricopeptide repeat (TPR) domain, a DUF3800 domain and, optionally, a UvrD polypeptide and an additional TPR polypeptide. CRISPR-Cas systems may comprise the Type V Cas polypeptide, or a composition thereof, and one or more guide molecules.
Described herein are hematopoietic cell-specific targeting moieties and compositions including the hematopoietic cell specific targeting motifs. Also described herein are uses of the hematopoietic cell-specific targeting motifs and compositions including the hematopoietic cell specific targeting moieties. In some embodiments, the hematopoietic cell-specific targeting moieties and compositions including the hematopoietic cell specific targeting moieties can be used to direct delivery of a cargo to a hematopoietic cell.
The present disclosure includes compositions and methods for treating cardiovascular disease (CVD) (e.g., cholesterol related disorders, or diseases caused or characterized by increased levels of plasma triglycerides, plasma cholesterol, or serum C-reactive protein), or symptoms thereof. The disclosure also includes compositions and methods for lowering plasma triglycerides in a subject, lowering plasma cholesterol levels in a subject, and lowering serum C-reactive protein levels in a subject.
This application discloses in part methods and compositions for mutating immune cells (e.g., CAR-T cells) and determining mutated immune cell cancer killing efficacy in vivo.
The present disclosure relates to electrophilic reactive linkers, which find utility labeling target substrates according to the formula L1-El, El-L1, or L1-El-L2, wherein El is an electrophilic reactive group and wherein L1 and L2 are linking molecules. Molecules according to the present invention find use, for example, in multifunctional chimeric molecules (e.g., bifunctional molecules), which make substrate modifications such as post-translational modifications to targets that are not the natural substrate; accordingly, diseases or disorders may be treated or prevented with molecules of the present disclosure.
A61K 47/55 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
32.
MULTI-SCALE FOOTPRINTING OF DNA-PROTEIN INTERACTIONS
Multi-scale footprinting of DNA-protein interactions is described. Multi-scale footprint scores may be generated based on chromatin accessibility data, the multi-scale footprint scores indicating protein binding to positions of a genome at different protein size scales. A deep learning model may be trained using the multi-scale footprint scores and corresponding DNA sequences. DNA-protein interactions for a DNA sequence of interest may be predicted using the trained deep learning model. The prediction may include generating sequence attribution scores for the DNA sequence of interest using the trained deep learning model and predicting transcription factor binding sites of the DNA sequence of interest based on the sequence attribution scores.
G16B 5/00 - ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
G16B 40/00 - ICT specially adapted for biostatisticsICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
Provided herein are methods of treating cancers, inflammatory diseases, and autoimmune diseases and methods of modulating related phenotypes and expression levels by targeting interactions among E3 ligases, E3-like proteins, and their interacting partners. Methods of identifying modulators of such interactions are also provided. Also provided herein are cell therapies comprising alterations in at least two members of a co-functional gene module.
C07K 16/00 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies
C07K 16/28 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA.
Aspects of the disclosure relate to methods, uses, compositions, kits, and systems for editing an endogenous tRNA into a suppressor tRNA. Additional aspects relate to compositions comprising the prime editing machinery, pegRNAs, and/or complexes comprising the prime editor and pegRNA that are capable of editing and/or replacing an endogenous tRNA to yield a suppressor tRNA. Polynucleotides, cells, vectors, and complexes are also contemplated.
Provided are recombinant adeno-associated virus (rAAV) vectors comprising a transgene to express human TSC1 (hamartin); viral particles comprising said vectors (rAAV particles); methods of their production, methods of their use, including methods for treating Tuberous Sclerosis Complex (TSC) caused by TSC1 gene mutations and symptoms arising therefrom; and kits.
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
A61P 9/10 - Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
37.
METHODS AND COMPOSITIONS FOR METHYLATION-SPECIFIC DUPLEX SEQUENCING
The disclosure provides a powerful new approach to dual-strand high-throughput next-generation methylation-specific sequencing. The disclosed method provides an enzymatically deaminated strand concatenated to the reverse complement of the other strand, which is protected from conversion by using conversion-resistant dCTPs (e.g., 5- hydroxycytosine, 5-carboxycytosine or 5-propargylaminocytosine) in the strand linking step. This enables both strands to be sequenced together, with mutations detected with duplex sequencing accuracy from both strands, and methylation detected from the converted strand.
Described and featured herein are antibodies that specifically bind to a phosphorylated S104 amino acid residue in a CARD9 polypeptide and methods of using such antibodies to identify subjects vulnerable to fungal infection, including fungal infections caused by Candida spp.
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences especially for use as to nucleotide repeat disorders. Provided are delivery systems and tissues or organ which are targeted as sites for delivery especially for use as to nucleotide repeat disorders. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex or system especially for use as to nucleotide repeat disorders, as well as methods for the design and of such. Also provided are methods of directing CRISPR complex or system formation in eukaryotic cells especially for use as to nucleotide repeat disorders including with consideration of specificity for target recognition and avoidance of toxicity and editing or modifying a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
The invention provides for systems, methods, and compositions for altering expression of target gene sequences and related gene products. Provided are structural information on the Cas protein of the CRISPR-Cas system, use of this information in generating modified components of the CRISPR complex, vectors and vector systems which encode one or more components or modified components of a CRISPR complex, as well as methods for the design and use of such vectors and components. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for utilizing the CRISPR-Cas system. In particular the present invention comprehends optimized functional CRISPR-Cas enzyme systems. In particular the present invention comprehends engineered new guide architectures to be used in optimized CRISPR-Cas enzyme systems.
Methods and compositions for analysis and treatment of repeat expansion disorders are described. Labeled amplicons of a variable repeat region of a gene may be generated, the generating using primers that introduce at least one molecular label to respective nucleic acid molecules of origin of a biological sample. The labeled amplicons may be sequenced to generate sequencing reads having the at least one molecular label incorporated. A sequence repeat length distribution of the variable repeat region in at least a portion of the biological sample may be generated based on the sequencing reads.
C12Q 1/6883 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
42.
DELIVERY, USE AND THERAPEUTIC APPLICATIONS OF THE CRISPR-CAS SYSTEMS AND COMPOSITIONS FOR TARGETING DISORDERS AND DISEASES USING PARTICLE DELIVERY COMPONENTS
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are delivery particle formulations and/or systems comprising one or more components of a CRISPR-Cas system, which are means for targeting sites for delivery. The delivery particle formulations of the invention are preferably nanoparticle delivery formulations and/or systems. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity and to edit or modify a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
The disclosure includes non-naturally occurring or engineered CRISPR Cas9, each associated with at least one destabilization domain (DD), along with compositions, systems and complexes involving the DD-CRISPR Cas9, nucleic acid molecules and vectors encoding the same, delivery systems involving the same, uses therefor.
A61K 9/00 - Medicinal preparations characterised by special physical form
A61K 9/1272 - Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
C12N 15/88 - Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using liposome vesicle
A61K 9/1271 - Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
45.
METHODS AND COMPOSITIONS FOR CELL-TYPE-SPECIFIC NUCLEIC ACID DELIVERY
Disclosed herein are modified RNAs comprising one or more one or more modified nucleotides at position +1 to position +6 with reference to a 5' terminus of the RNA, and methods of making the same. Also provided are compositions comprising one or more of the modified RNAs provided herein, and methods of using said compositions for therapeutic applications.
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
A61K 47/69 - Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additivesTargeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
46.
LIGATION-FREE METHODS FOR CHEMICAL AND TOPOLOGICAL MODIFICATION OF RNA
Disclosed herein are topologically modified RNA molecules, and methods of making the same. Also provided are compositions comprising one or more of the topologically modified RNA transcripts provided herein, and methods of using said compositions for therapeutic applications.
C12N 15/11 - DNA or RNA fragmentsModified forms thereof
C07H 21/02 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
C12P 19/34 - Polynucleotides, e.g. nucleic acids, oligoribonucleotides
47.
PRIME EDITING METHODS AND COMPOSITIONS FOR THE TREATMENT OF RETINITIS PIGMENTOSA
The present disclosure provides methods of editing RHO using a prime editor (e.g., for correcting a P23H mutation in a RHO protein) and a pegRNA. Such methods may be useful for treating or preventing retinitis pigmentosa. The present disclosure also provides pegRNAs, ngRNAs, complexes, systems, and compositions for editing RHO and treating or preventing retinitis pigmentosa. Polynucleotides, vectors, cells, and kits for editing RHO and treating or preventing retinitis pigmentosa are also provided herein.
C12N 15/00 - Mutation or genetic engineeringDNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purificationUse of hosts therefor
48.
ENGINEERED PRIME EDITING GUIDE RNAS AND METHODS OF MAKING AND USING SAME
The present disclosure provides engineered prime editing guide RNAs (pegRNAs) comprising new 3 ' motifs useful for increasing prime editing efficiency. The present disclosure also provides systems for prime editing using the disclosed pegRNAs. Polynucleotides and vectors encoding the pegRNAs are also provided herein. The present disclosure also provides cells, compositions, and kits comprising the pegRNAs. Methods of prime editing using the pegRNAs are also provided herein. The present disclosure further provides for the use of the pegRNAs in medicine or in the manufacture of a medicament for treating a disease or disorder.
Provided herein are polynucleotides, vectors, complexes, compositions, systems, kits, methods and uses for enriching for gene editing in a cell. Some aspects of the disclosure relate to the use of a polynucleotide cassette comprising a coding sequence of a selection marker gene that is disrupted by a synthetic intron sequence to prevent gene expression of the selection marker. The synthetic intron further comprises a defective splice site that is correctable by a base edit such that when the splice site is corrected by a gene editor, the intron is removed by the endogenous slicing system of the cell and expression of the selection marker gene can occur. Methods described herein screen for the presence of active gene editors within the cell by subjecting the cell to the selection pressure of the selection marker.
Systems, methods and composition for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising novel TnpB polypeptides and a reprogrammable targeting nucleic acid component and methods and application of use are provided.
Paired index position-encoded sequencing is described. A plurality of transposons may be generated, each of the plurality of transposons comprising two oligonucleotides coupled together in a 5'-to-5' orientation to encode a unique pair of index sequences that distinguishes one transposon of the plurality of transposons from other transposons of the plurality of transposons. The plurality of transposons may be integrated into genomic DNA during a sequencing workflow. The unique pair of index sequences of the plurality of transposons may be matched between sequencing reads obtained during the sequencing workflow. A genomic sequence of the biological sample may be reconstructed based on the matching.
Applicants address the challenge of antibodies that recognize AAVs and can prevent transduction into targeted tissues and cells. Binding antibodies can also increase the risk of complement activation and thrombotic microangiopathy (TMA), therefore many subjects with pre-existing immunity are excluded from receiving AAV related therapies. Applicants modify capsids through the introduction of surface amino acid substitutions designed to reduce their recognition by pre-existing antibodies in humans. Applicants describe novel antibody evading (AE) capsids that maintain transduction activity in the presence of human sera that neutralize the natural serotypes, for example, AAV9 and AAV5.
Electrocardiogram-based deep learning for cardiac prediction is described. An electrocardiogram analysis module may include a data preprocessor configured to normalize an electrocardiogram to generate a standardized input for an electrocardiogram-based cardiac prediction. The electrocardiogram analysis module may further include a deep learning model including a neural network and at least one dense layer, the deep learning model trained to identify features associated with a cardiac condition that reflect underlying cardiac changes that result from or predispose development of the cardiac condition, and generate a cardiac prediction based on the identified features.
The invention, in some aspects, includes systems, methods and components of molecular recorders that encode the timing of transcriptional activity into the sequence of RNA, which can then enable a sequencing-based readout of the internal dynamics of cells.
Electrocardiogram-based deep learning for hypertension prediction is described. An electrocardiogram analysis module may include a data preprocessor configured to normalize an electrocardiogram to generate a standardized input for electrocardiogram-based hypertension prediction. The electrocardiogram analysis module may further include a deep learning model including a neural network trained to identify features associated with hypertension from the standardized input and at least one dense layer trained to generate a hypertension risk prediction based on the identified features. The hypertension risk prediction may comprise a probability score indicating a likelihood of hypertension.
Described herein are targeting moieties that can be capable of specifically targeting muscle cells and can include an n-mer motif. In some embodiments, the n-mer motif contains an RGD motif. Also described herein are vector systems, particles, polypeptides that can encode and/or contain one or more targeting moieties. Also described herein are methods of delivering a cargo to a cell, such as a muscle cell, using one or more of the targeting moieties described herein.
A61K 31/7088 - Compounds having three or more nucleosides or nucleotides
A61K 47/64 - Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
C07K 7/06 - Linear peptides containing only normal peptide links having 5 to 11 amino acids
C07K 14/005 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from viruses
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
Compositions and methods that are useful for inducing phagocytosis of a cancer cell and/or increasing killing of a cancer cell (e.g., by an immune cell) by contacting the cancer cell with an antibody capable of selectively binding to a CD43 protein expressed on the surface of cancer cells. In various embodiments, the CD43 protein is not expressed on the surface of a healthy cell.
C07K 16/28 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
Methods and compositions capable of obtaining paired transcriptome and genotype information from single cells in high throughput are provided. Disclosed methods and compositions obtain paired transcriptome and genotype information from single cells in a manner that is highly sensitive, capable of detecting even very low-level transcripts in single cells, and associating such low-level transcripts and abundance information with associated genotypes, within a single cell.
Systems, methods and compositions for targeting polynucleotides are detailed herein. In particular, engineered DNA-targeting systems comprising IscB polypeptides, novel IscB nucleases and reprogrammable targeting nucleic acid components and methods and application of use are rovided.
Methods for single-cell DNA methylation profiling are disclosed herein, with embodiments featuring use of droplet-based cell barcoding and conversion reagents to generate high-quality methylomes and/or methylome-plus-transcriptomes, for single cell genomic analysis and correlation of methylation state with transcript expression levels at single-cell resolution. The present disclosure is based, at least in part, upon discovery of methods and compositions capable of leveraging cell barcoding and conversion reagents to generate high-quality single-cell methylomes capable of being assessed rapidly in parallel across populations of cells, as well as coordinated single-cell methylome-plus-transcriptomes formatted for parallel, high-throughput assessment of cellular populations with precise single-cell resolution.
The present disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be glycogen synthase kinase 3 (GSK3) inhibitors. The present disclosure also provides pharmaceutical compositions, combination therapies, and kits comprising the compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and methods of treating or preventing diseases and disorders associated with GSK3.
The present disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be glycogen synthase kinase 3 (GSK3) inhibitors. The present disclosure also provides pharmaceutical compositions, combination therapies, and kits comprising the compounds, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, or prodrugs thereof, and methods of treating or preventing diseases and disorders associated with GSK3.
A61K 31/4375 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring hetero atom, e.g. quinolizines, naphthyridines, berberine, vincamine
A61K 31/438 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring being spiro-condensed with carbocyclic or heterocyclic ring systems
A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
A61K 31/501 - PyridazinesHydrogenated pyridazines not condensed and containing further heterocyclic rings
A61K 31/506 - PyrimidinesHydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
Immune effector cells (e.g., immune effector cells, or immune effector cells, such as T cells), that have been modified to reduce or render undetectable expression of a polypeptide (e.g., GNA13, LEF1, PTPN2, RASA2, SMAD2, SOCS1, TBL1XR1, TGFBR2, and UBASH3A), and methods for use thereof to treat a disease (e.g., a neoplasia). In some embodiments, the modified immune effector cells express a chimeric antigen receptor (CAR). In various embodiments, the polypeptide is GNA13, LEF1, PTPN2, RASA2, SMAD2, SOCS1, TBL1XR1, TGFBR2, and UBASH3A knocked out using CRISPR technology.
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
C07K 14/71 - ReceptorsCell surface antigensCell surface determinants for growth factorsReceptorsCell surface antigensCell surface determinants for growth regulators
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
Compositions and methods for detecting bacterial pathogens containing microbial resistance genes in a sample, as well as methods for selecting a treatment for human infections involving such organisms. The methods involve carrying out a series of reactions in parallel where each reaction involves detecting a bacterial species or resistance gene in a sample using a CRISPR-Cas13a reaction. In some embodiments, the methods involve culturing a blood sample to increase the concentration of bacteria in the sample and/or direct detection of bacterial pathogens and/or microbial resistance genes in a blood sample.
C12Q 1/689 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for detection or identification of organisms for bacteria
Immunogenic compositions comprising one or more peptides, wherein the one or more peptides: are capable of binding to Major Histocompatibility Complex (MHC) class II, and are derived from one or more translation products of SARS-CoV-2. Also provided include methods of treating and preventing diseases using the immunogenic compositions.
The present disclosure provides base editor fusion proteins, complexes, and systems capable of installation of multiple edits across large genomic windows (e.g., between 4bps and 500 bps) and which may be useful, for example, for mutating one or more nucleotides in a target nucleic acid. The disclosure describes gene editing systems comprising a first fusion protein comprising a C-terminal portion of a split deaminase and a first epitope binding domain, a second fusion protein comprising a N-terminal portion of a split deaminase and a second epitope binding domain, and a third fusion protein comprising a DNA binding protein domain and one or more epitope domains to which the first and second fusion proteins may bind (along the one or more epitope domains), thereby forming an active deaminase domain. The base editor fusion proteins, complexes and systems can be used in certain embodiments in methods of performing mutational screens in a gene of interest. Other aspects of the disclosure relate to methods, for example, methods of mutating one or more nucleotides in a target nucleic acid and methods of performing mutational screens. The disclosure also provides compositions, polynucleotides, vectors, pharmaceutical compositions, cells, kits, and systems comprising the base editor fusion proteins and complexes contemplated herein.
Single domain VHH polypeptides (antibodies) that bind Claudin-18 (e.g., Claudin-18.2), VHH polypeptide products, methods, cells, pharmaceutical compositions, and kits. The VHH polypeptides may be recombinantly produced and expressed. Provided are also chimeric antigen receptor (CAR) polypeptides comprising the VHH polypeptides and CAR immune effector cells comprising the expressing the same.
C07K 16/28 - Immunoglobulins, e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
A61K 40/11 - T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cellsLymphokine-activated killer [LAK] cells
Described herein are engineered, non-naturally occurring systems and compositions comprising multimeric CRISPR-Cas complexes comprising a β-CASP polypeptide, a plurality of Cas polypeptides, and a guide molecule, packaging and delivery systems thereof, and methods of use thereof, for modifying target polynucleotides. In addition, described herein are engineered, non-naturally occurring systems and compositions comprising a class of small Cas proteins (Type II-B, II-C, and II-D Cas proteins) and methods of modifying target sequences using the Type II-B, II-C, II-D Cas proteins and systems thereof.
PRNPPRNPPRNP gene — e.g., in the promoter, promoter-proximal, or coding sequence — to reduce or abolish PrP expression and/or activity. In certain embodiments, the reduction of PrP activity may occur through inhibition of PRNP transcription, disruption of translation (e.g., by editing the start codon), or generation of a truncated PrP variant that lacks misfolding and aggregation properties characteristic of PrPSc. These compositions and methods are useful for preventing, treating, or ameliorating prion disease.
Provided are compositions and methods for delivering biological moieties such as modified nucleic acids into cells to kill or reduce the growth of microorganisms. Such compositions and methods include the use of modified messenger RNAs, and are useful to treat or prevent microbial infection, or to improve a subject's heath or wellbeing.
The Trustees of Columbia University in the City of New York (USA)
The Broad Institute, Inc. (USA)
Inventor
Pernice, Wolfgang M.
Hirano, Michio
Caicedo, Juan C.
Abstract
The present disclosure relates to a method for generating a training set based on a first set of images and a second set of images, each image having a respective observational environment and a respective feature set. The method includes (a) obtaining, by a generator module, the first set of images and the second set of images; (b) extracting, by the generator module, one or more feature sets from each image in the first set of images; (c) extracting, by the generator module, one or more respective observational environments from each image in the second set of images; (d) deriving, by an encoder module, one or more latent representations from the one or more feature sets extracted from one or more images in the first set of images; (e) deriving, by the encoder module, one or more style codes from the one or more respective observational environment extracted from one or more images in the second set of images; (f) generating, by the generator module, an interventional training distribution having samples including each respective one or more style codes and each one or more latent representations; and, (g) storing, by the generator module, the interventional training distribution training set.
G06T 11/60 - Editing figures and textCombining figures or text
G06V 10/77 - Processing image or video features in feature spacesArrangements for image or video recognition or understanding using pattern recognition or machine learning using data integration or data reduction, e.g. principal component analysis [PCA] or independent component analysis [ICA] or self-organising maps [SOM]Blind source separation
71.
RNA PROGRAMMABLE EPIGENETIC RNA MODIFIERS AND USES THEREOF
The disclosure provides programmable methylation “writers” and demethylation “erasers” for editing the methylation state of RNA targets, e.g., an RNA transcriptome. In particular, the disclosure provides RNA methylation editor polynucleotide constructs and vectors comprising (i) an RNA programmable RNA binding domain (RNApRNAbd); and (ii) an effector domain, wherein the effector domain is capable of adding or removing a methyl group in an RNA. The disclosed RNA methylation editor constructs are capable of achieving limited off-target modifications in RNA molecules. Further, the disclosure provides methods for making and using the programmable methylation editors to modifying the methylation state of RNA. The disclosure further provides complexes comprising a methylation writer protein and a guide RNA molecule and complexes comprising a demethylation eraser protein and a guide RNA molecule. The disclosure further provides pharmaceutical compositions and cells comprising the disclosed fusion proteins and complexes.
The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.
The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.
The disclosure relates generally to methods and compositions for cryopreservation and processing of blood for single-cell RNA-sequencing. More particularly, the disclosure relates to methods and compositions for preserving and processing whole blood to enable diagnosing and/or treating sepsis via single-cell RNA sequencing (scRNA-seq). In certain aspects, the methods and compositions disclosed herein may be employed in diagnosis and treatment of subjects having or at risk of having sepsis.
The present disclosure relates to compositions and methods for tracking and spatially localizing a cell-expressed fusion protein within the cell (with the fusion protein optionally associated with a subcellular compartment, organelle, synapse, or the like), in a manner that minimizes any disruptive impact upon the cell, at least until the detection process is initiated. Use of transcriptomics and/or barcode nucleic acid detection is employed to assess both spatial localization of intracellularly tagged fusion proteins and to establish cell-cell connectivity, e.g., in neurons across a synapse, by associating axonal identities with individual neurons at the molecular tag and transcriptome level.
C12Q 1/6874 - Methods for sequencing involving nucleic acid arrays, e.g. sequencing by hybridisation [SBH]
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
Described herein are targeting moieties that can be capable of specifically targeting muscle cells and can include an n-mer motif. In some embodiments, the n-mer motif contains an RGD motif. Also described herein are vector systems, particles, polypeptides that can encode and/or contain one or more targeting moieties. Also described herein are methods of delivering a cargo to a cell, such as a muscle cell, using one or more of the targeting moieties described herein.
A61K 31/7088 - Compounds having three or more nucleosides or nucleotides
A61K 47/64 - Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
A61K 48/00 - Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseasesGene therapy
C07K 7/06 - Linear peptides containing only normal peptide links having 5 to 11 amino acids
C07K 14/005 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from viruses
C07K 14/47 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from mammals
Described herein are methods of generating engineered viral capsid variants. Also described herein are engineered viral capsid variants, engineered viral particles and formulations and cells thereof. Also described herein are vector systems containing an engineered viral capsid polynucleotide and uses thereof.
The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA. Aspects of the invention in particular relate to Cpf1 mutants having altered PAM specificity.
Provided herein are computer-implemented methods for assigning maternal or fetal origin to one or more genetic variants in cell free DNA (cfDNA) from a sample from a pregnant mammal, preferably a pregnant human, using a probabilistic model for assigning maternal or fetal origin to genetic variants in DNA from a sample obtained from a pregnant mammal, wherein the model assigns maternal or fetal origin based on a combination of fetal fraction and DNA fragment size.
C12Q 1/48 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving transferase
C12Q 1/6806 - Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
C12Q 1/6876 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
G16B 5/00 - ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
G16H 10/40 - ICT specially adapted for the handling or processing of patient-related medical or healthcare data for data related to laboratory analysis, e.g. patient specimen analysis
G16H 10/60 - ICT specially adapted for the handling or processing of patient-related medical or healthcare data for patient-specific data, e.g. for electronic patient records
G16H 50/30 - ICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indicesICT specially adapted for medical diagnosis, medical simulation or medical data miningICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for individual health risk assessment
The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]
Described in certain embodiments herein are computer implemented methods, systems, and computer program products that can be used to identify or engineered cell specific cis-regulatory elements (CREs). Also described herein are cell specific CREs and uses thereof.
The embodiments disclosed herein utilize RNA targeting effectors to provide a robust CRISPR-based diagnostic for hemorrhagic fever virus applications. Embodiments disclosed herein can differentiate between hemorrhagic fever viruses that present with similar symptoms, as well as between strains of a hemorrhagic fever virus.
C12Q 1/70 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving virus or bacteriophage
The present disclosure features methods for modifying fertility. In some embodiments, the disclosure provides contraceptive compositions and methods of using the same.
The present invention relates to 1H-pyrrolo[3,2-b]pyridine derivatives of formula (I) as irreversible inhibitors of mutant EGFR for the treatment of cancer. An exemplary compound is e.g. N-[2-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyri-din-3-yl}oxy)ethyl]prop-2-enamide (example 1). Pharmacological data of exemplary compounds is provided (AA).
The present invention relates to 1H-pyrrolo[3,2-b]pyridine derivatives of formula (I) as irreversible inhibitors of mutant EGFR for the treatment of cancer. An exemplary compound is e.g. N-[2-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyri-din-3-yl}oxy)ethyl]prop-2-enamide (example 1). Pharmacological data of exemplary compounds is provided (AA).
The present invention relates to 1H-pyrrolo[3,2-b]pyridine derivatives of formula (I) as irreversible inhibitors of mutant EGFR for the treatment of cancer. An exemplary compound is e.g. N-[2-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyri-din-3-yl}oxy)ethyl]prop-2-enamide (example 1). Pharmacological data of exemplary compounds is provided (AA).
mutEGFR
mutEGFR
(D770_N771insSVD)
(D770_N771insNPG,
kinase assay
T790) kinase assay
Example
IC50
IC50
No.
[mol/l]
[mol/l]
1
4.14E−07
6.06E−07
2
4.61E−07
7.51E−07
3
2.84E−06
3.41E−06
4
7.58E−09
1.71E−08
(AA)
A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/4545 - Non-condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/4709 - Non-condensed quinolines containing further heterocyclic rings
A61K 31/5377 - 1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
C12Q 1/6886 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
This disclosure relates to novel PRNP targeting sequences. Novel PRNP targeting oligonucleotides for the treatment of neurodegenerative diseases are also provided.
A61P 25/28 - Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
85.
ENGINEERED TYPE II CAS POLYNUCLEOTIDES WITH REDUCED IMMUNOGENICITY AND USES THEREOF
Engineered Type II Cas polypeptides with reduced immunogenicity, CRISPR-Cas systems thereof, compositions thereof, delivery systems thereof, and methods of use thereof for modifying target polynucleotides, such as, for example, in cells.
Methods for treating leukemia are disclosed based on detecting specific cell states and transcriptional programs within leukemic cells. This disclosure presents a novel therapeutic method for treating acute lymphoblastic leukemia (ALL), including BCR-ABL positive and BCR-ABL1-like ALL subtypes. The method involves detecting specific cell states and transcriptional programs in patient samples and administering targeted therapies based on these characteristics. For a pre-B cell-like state or pre-BCR signaling program, a combination of tyrosine kinase inhibitor (TKI) and SYK inhibitor is used. Conversely, a progenitor-like state or stress-autophagy program is treated with a TKI and a p38 MAPK inhibitor. This approach aims to improve treatment efficacy by tailoring therapy to the leukemia's unique molecular and cellular features, particularly in relapsed cases or when minimal residual disease is present.
C12Q 1/6886 - Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
A61K 31/00 - Medicinal preparations containing organic active ingredients
A61P 35/02 - Antineoplastic agents specific for leukemia
87.
COMPOSITIONS AND METHODS FOR PRODUCTION OF DOUBLE-STRANDED DNA IN CELLS FOR PROGRAMMABLE GENE INTEGRATION
The present disclosure provides systems, compositions, and methods for producing double-stranded DNA in a cell. Further provided herein are polynucleotides, vectors, compositions, cells, and kits for use in the present systems and methods.
The present disclosure provides compositions and methods for conjugating a target polypeptide and a target oligonucleotide. More particularly, the present disclosure provides compositions and methods for making and using a recombinant protein harboring a domain recognizing a nucleic acid and a domain capable of binding and crosslinking with antigen-binding polypeptides.
The invention provides for systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for selecting specific cells by introducing precise mutations utilizing the CRISPR/Cas system.
A method of identifying therapeutic agent for the treatment of a cancer with a KIAA1549-BRAF fusion is disclosed. The method includes contacting a cell expressing a KIAA1549-BRAF fusion protein with a test agent and determining if the test agent inhibits O-mannosylation of the KIAA1549-BRAF fusion protein, inhibits heterodimerization of protein O-mannosyltransferase 1 (POMT1) and protein O-mannosyltransferase 2 (POMT2), and/or inhibits activity of the protein O-mannosyl transferase (POMT) complex in the cell expressing a KIAA1549-BRAF fusion protein. A therapeutic agent and its use for the treatment of a cancer comprising a KIAA1549-BRAF fusion is also disclosed.
C12Q 1/48 - Measuring or testing processes involving enzymes, nucleic acids or microorganismsCompositions thereforProcesses of preparing such compositions involving transferase
C07D 417/12 - Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group containing two hetero rings linked by a chain containing hetero atoms as chain links
A61K 45/06 - Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
G01N 33/574 - ImmunoassayBiospecific binding assayMaterials therefor for cancer
92.
TYPE I-D CRISPR-ASSOCIATED TRANSPOSASE AND TYROSINE RECOMBINASE TRANSPOSON SYSTEMS
The invention provides for systems and methods for inserting large polynucleotides into precise locations in a target polynucleotide. In one aspect, the systems comprise an engineered Type I-D/Tn7 CRISPR-associated transposase system (CAST) comprising a Tn7-like transposase linked to or otherwise capable of associating with a Type I-D CRISPR-Cas complex (Tn7-CAST I-D). In another aspect, the systems comprise a Tn7-like transposase comprising a modular target site selection protein, called TnsF, that may be engineered to reprogram the Tn7-like transposase to facilitate insertion at different sites in a target polynucleotide. In another aspect, the systems comprise a transposon system comprising a tyrosine recombinase which provides for scar-less insertion of large donor sequences into target polynucleotides. Also provided are methods for modifying target polynucleotides using the systems; polynucleotides encoding the systems; delivery systems for delivering the components of the systems; and cells and biological products modified by or modified to include the systems.
Systems and methods for targeted gene modification, targeted insertion, perturbation of gene transcripts, and nucleic acid editing. Novel nucleic acid targeting systems comprise components of CRISPR systems and non-LTR retrotransposon elements.
C07K 14/435 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans
C07K 14/465 - Peptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from animalsPeptides having more than 20 amino acidsGastrinsSomatostatinsMelanotropinsDerivatives thereof from humans from vertebrates from birds
Aspects of the disclosure relate to methods, compositions, and systems for editing an endogenous tRNA into a suppressor tRNA, or alternatively, replacing said endogenous tRNA with a suppressor tRNA with using prime editing. Additional aspects relate to compositions comprising the prime editing machinery, pegRNAs, and/or complexes comprising the prime editor and pegRNA that are capable of editing and/or replacing an endogenous tRNA to yield a suppressor tRNA. In some aspects, the disclosure further relates to polynucleotides encoding one or more nucleic acid sequences encoding the prime editor and/or pegRNA, cells comprising the polynucleotides and complexes comprising the prime editor and pegRNA, kits comprising any one of the compositions, complexes, polynucleotides, vectors, and/or cells disclosed herein, and/or delivery systems for administering any one of the compositions, complexes, polynucleotides, vectors to a subject in need thereof. Additional aspects relate to methods for inserting a new suppressor tRNA gene into a target site in a genome (e.g., a safe harbor locus site) using prime editing.
The technology described herein provides tissue dissociation well plates, devices, systems, and kits to isolate single-cells or a single-nuclei using wells with roughened, angled bottom surfaces to receive pipette tips delivering tissue samples and isolation buffers. In certain examples, the bottom surfaces of the wells are roughened to aid in breaking down the tissue sample. In other examples, the tip of the pipette is roughened or serrated to aid in breaking down the tissue sample. The wells may be arrayed in a solid rigid upper surface. The pipette tips deliver isolation buffers and/or dissociation fluids to the wells and the tissue samples. The fluid delivery is provided by pumps via one or more perfusion manifolds. A pipette adaptor raises, lowers, and twists the pipette tips. The pipette tips deliver the dissociation fluid, withdraw the tissue samples with a suction force, and return the tissue samples to the well with an expelling force. The pipette tips may be twisted to provide an additional force to break down the tissue sample.
Disclosed herein are branched RNA oligonucleotides and methods of making the same. The branched RNA oligonucleotides may be made by using a brancher phosphoramidite. Also provided are compositions comprising one or more of the branched RNA oligonucleotides provided herein, and methods of using said compositions for therapeutic applications.
C07H 1/00 - Processes for the preparation of sugar derivatives
C07H 19/073 - Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
C07H 21/04 - Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
97.
DELIVERY, ENGINEERING AND OPTIMIZATION OF SYSTEMS, METHODS AND COMPOSITIONS FOR SEQUENCE MANIPULATION AND THERAPEUTIC APPLICATIONS
The invention provides for delivery, engineering and optimization of systems, methods and compositions for manipulation of sequences and/or activities of target sequences. Provided are delivery systems and tissues or organ which are targeted as sites for delivery. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity and to edit or modify a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
The present invention discloses novel pentamidine analogues such as pentamidine analogs having the general formula:
The present invention discloses novel pentamidine analogues such as pentamidine analogs having the general formula:
The present invention discloses novel pentamidine analogues such as pentamidine analogs having the general formula:
wherein:
X is C, N, or —CH—CH—,
Y is Y1 when X is N, and Y is Y1 and Y2 when X is C, or —CH—CH—,
Y1, or Y1 and Y2 independently, are selected from H, hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano or thiol, wherein the lower alkyl or alkoxy is optionally substituted with one or more of hydroxyl, halogen, nitro, amino, cyano, thiol, or a 5- or 6-membered aromatic or non-aromatic ring, optionally substituted with one or more of hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano or thiol, wherein Y1 is not H when X is N; or
Y1 is a 5- or 6-membered aromatic or non-aromatic ring, optionally substituted with one or more groups selected from hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano, carboxy, or thiol, and Y2 is H, if present; or
Y1 and Y2 together with X form a 5- to 8-membered hydrocarbon ring, optionally substituted with one or more groups selected from hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano, carboxyl, or thiol;
Z is phenyl, optionally substituted with one or more groups selected from hydroxyl, lower alkyl, lower alkoxy, halogen, nitro, amino, cyano, carboxyl, or thiol; and
R1 to R4 are each independently H, hydroxyl, halogen, lower alkyl or lower alkoxy;
as well as related pentamidine analogs and their use to inhibit bacterial growth and treat bacterial infection.
C07C 257/18 - Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
A61K 31/40 - Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
A61K 31/4178 - 1,3-Diazoles not condensed and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
A61K 31/444 - Non-condensed pyridinesHydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. amrinone
A61K 31/451 - Non-condensed piperidines, e.g. piperocaine having a carbocyclic ring directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
A61K 31/7048 - Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin
C07D 211/34 - Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
C07D 213/78 - Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
C07D 233/64 - Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
C07D 295/155 - Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
99.
SELF-ASSEMBLING VIRUS-LIKE PARTICLES FOR DELIVERY OF NUCLEIC ACID PROGRAMMABLE FUSION PROTEINS AND METHODS OF MAKING AND USING SAME
The present disclosure provides virus-like particles for delivering gene editing agents such as nucleic acid-programmable DNA-binding proteins (napDNAbps) and base editor fusion proteins (“BE-VLPs” or “eVLPs”), and systems comprising such eVLPs. The present disclosure also provides polynucleotides encoding the eVLPs described herein, which may be useful for producing said eVLPs. Also provided herein are methods for editing the genome of a target cell by introducing the presently described eVLPs into the target cell. The present disclosure also provides fusion proteins that make up a component of the eVLPs described herein, as well as polynucleotides, vectors, cells, and kits.
The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are delivery systems and tissues or organ which are targeted as sites for delivery. Also provided are vectors and vector systems some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity and to edit or modify a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.
C12N 15/01 - Preparation of mutants without inserting foreign genetic material thereinScreening processes therefor
C12N 15/10 - Processes for the isolation, preparation or purification of DNA or RNA
C12N 15/113 - Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides
C12N 15/63 - Introduction of foreign genetic material using vectorsVectorsUse of hosts thereforRegulation of expression
G06Q 50/00 - Information and communication technology [ICT] specially adapted for implementation of business processes of specific business sectors, e.g. utilities or tourism
H04L 51/52 - User-to-user messaging in packet-switching networks, transmitted according to store-and-forward or real-time protocols, e.g. e-mail for supporting social networking services
H04L 65/1069 - Session establishment or de-establishment
